miglustat

ミグルスタット

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/09/24 19:07:52」(JST)

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Miglustat

Systematic (IUPAC) name
(2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a604015
Licence data	US FDA:link
Pregnancy cat.	X (US)
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	97%
Protein binding	Nil
Metabolism	Nil
Half-life	6–7 hours
Excretion	Renal, unchanged
Identifiers
CAS number	72599-27-0 Y
ATC code	A16AX06
PubChem	CID 51634
DrugBank	DB00419
ChemSpider	46764 Y
UNII	ADN3S497AZ Y
ChEBI	CHEBI:50381 Y
ChEMBL	CHEMBL1029 Y
Synonyms	1,5-(butylimino)-1,5-dideoxy-D-glucitol, N-butyl-deoxynojirimycin
Chemical data
Formula	C10H21NO4
Mol. mass	219.28 g/mol
SMILES OC[C@H]1N(CCCC)C[C@H](O)[C@@H](O)[C@@H]1O
InChI InChI=1S/C10H21NO4/c1-2-3-4-11-5-8(13)10(15)9(14)7(11)6-12/h7-10,12-15H,2-6H2,1H3/t7-,8+,9-,10-/m1/s1 Y Key:UQRORFVVSGFNRO-UTINFBMNSA-N Y
Y (what is this?)  (verify)

Miglustat is a drug developed by Actelion and is used primarily to treat Type 1 Gaucher disease (GD1). It is marketed under the trade name Zavesca. Miglustat (OGT 918, N-butyl-deoxynojirimycin) is an imino sugar (molecular weight: 219 daltons), a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste The primary pharmacological activity of miglustat is inhibition of the enzyme glucosylceramide synthase, catalyzing the first step in the biosynthesis of glycosphingolipids (GSL), i.e., the formation of glucosylceramide (GlcCer). Reduced formation of GlcCer will lead to decreased biosynthesis of more complex GSL. This therapeutic principle, called substrate reduction therapy (SRT), may be useful in disorders of intracellular (predominantly lysosomal) accumulation of GSL either due to their deficient breakdown or intracellular transport/trafficking. Miglustat exhibits a large volume of distribution and has the capacity to access deep organs such as the brain, bone and lung.

Miglustat inhibits glucosylceramide synthase, an essential enzyme for the synthesis of most glycosphingolipids. Miglustat is a glucosylceramide synthase inhibitor. It works by inhibiting glucosylceramide synthase (the enzyme that forms glucosylceramide, which accumulates within the macrophages). Miglustat is used to treat adults with mild to moderate type 1 Gaucher disease and it is the first treatment to be approved for patients with Niemann-Pick type C disease. Miglustat may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable and it's been approved in the European Union for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC). It has also been approved for NPC treatment in Canada, Switzerland, Brazil, Australia, Turkey and Israel but not in the United States.

Type 1 Gaucher disease is an autosomal recessive disorder one gets from both parents. People with type 1 Gaucher have a defect in the enzyme called glucocerebrosidase (also known as acid β-glucosidase) that acts on a fatty substance glucosylceramide (also known as glucocerebroside). Accumulation of glucosylceramide causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. Treatment with miglustat is known as substrate reduction therapy (SRT). Unlike enzyme replacement therapy (ERT), which has a direct effect on the breakdown of glycosphingolipids, the concept of SRT in Gaucher disease involves reduction of the delivery of potential storage material to the macrophage system. Patients treated with miglustat for 3 years show signicant improvements in organ volumes and haematological parameters. Miglustat was effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years. It is also being investigated to treat Tay-sachs disease, particularly late-onset Tay-Sachs. In October 2007, Actelion initiated a Phase IIa proof-of-concept clinical trial with Miglustat in cystic fibrosis (CF). It is the first time that Miglustat is being tested in a clinical setting involving 25 CF patients affected by the specific delF508 mutation.

Biosynthesis of Miglustat

Miglustate is a synthetic derivative of a family of polyhydroxylated alkaloids or amino sugar extracted from plants and microorganisms. The synthesis for it starts from D-glucose sugar in plants . The sugar then aminated and then oxidized to amino fructose sugar, which can then form a cyclic aminohemiacetal called nojirimycin. Then the dehydration and reduction takes place successively before the formation of deoxynojirimycin , which is the precursor of miglustat. Since it is the synthetic derivative drug, alkylation of “’deoxynojirimycin”’ can be synthesized in the laboratory with 1-butyl halide via Amine alkylation

This image of a simple structural formula is ineligible for copyright and therefore in the public domain, because it consists entirely of individual words, simple geometric shapes and information that is common property and contains no original authorship.

See also

• Isofagomine tartrate, another orphan drug for the treatment of Gaucher's disease with a similar chemical structure, but a different mechanism of action
• Miglitol, an oral antidiabetic drug with a similar structure

References

UpToDate Contents

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• 1. ゴーシェ病：治療 gaucher disease treatment
• 2. ニーマン・ピック病の概要 overview of niemann pick disease
• 3. ダリエ病 darier disease
• 4. 慢性B型肝炎ウイルス感染の試験研究中の治療 investigational treatments of chronic hepatitis b virus infection
• 5. ムコ多糖症：合併症およびマネージメント mucopolysaccharidoses complications and management

English Journal

• Enhanced F508del-CFTR Channel Activity Ameliorates Bone Pathology in Murine Cystic Fibrosis.

• Le Henaff C1, Haÿ E2, Velard F1, Marty C2, Tabary O3, Marie PJ4, Jacquot JP5.Author information 1EA 4691 "Biomatériaux et inflammation en site osseux" SFR CAP-Santé (FED 4231) and University Reims Champagne Ardenne, Reims, France.2Inserm UMR 606 and University Paris Diderot, Sorbonne Paris Cité, Paris, France.3Inserm U 938 and University Pierre Marie Curie, Paris, France.4Inserm UMR 606 and University Paris Diderot, Sorbonne Paris Cité, Paris, France. Electronic address: pierre.marie@inserm.fr.5EA 4691 "Biomatériaux et inflammation en site osseux" SFR CAP-Santé (FED 4231) and University Reims Champagne Ardenne, Reims, France. Electronic address: jacky.jacquot@inserm.fr.AbstractIn patients with cystic fibrosis (CF), rib and thoracic vertebral fractures can have adverse effects on lung health because the resulting pain and debilitation can impair airway clearance. The F508del mutation in the CF transmembrane conductance regulator (Cftr) gene induces an osteopenic phenotype in humans and mice. N-butyldeoxynojyrimicin (miglustat), an approved drug for treating type 1 Gaucher disease, was found to normalize CFTR-dependent chloride transport in human F508del CFTR lung cells and in nasal mucosa of F508del CF mice. Herein, we investigated whether targeting F508del-CFTR may rescue the skeletal osteopenic phenotype in murine CF. We found that oral administration of low-dose miglustat (120 mg/kg once a day for 28 days) improved bone mass and microarchitecture in the lumbar spine and femur in F508del mice. The increased bone density was associated with an increased bone formation rate and reduced bone resorption. This effect was associated with increased 17β-estradiol but not with insulin-like growth factor 1 serum levels in miglustat-treated F508del mice. Exposure of primary F508del osteoblasts to miglustat partially restored the deficient CFTR-dependent chloride transport in these bone-forming cells. This study provides evidence that reversal of CFTR-dependent chloride transport in osteoblasts normalizes bone mass and microarchitecture in murine CF. These findings may provide a potential therapeutic strategy to prevent or correct the bone disease in patients with CF.
• The American journal of pathology.Am J Pathol.2014 Apr;184(4):1132-41. doi: 10.1016/j.ajpath.2013.12.027. Epub 2014 Feb 11.
• In patients with cystic fibrosis (CF), rib and thoracic vertebral fractures can have adverse effects on lung health because the resulting pain and debilitation can impair airway clearance. The F508del mutation in the CF transmembrane conductance regulator (Cftr) gene induces an osteopenic phenotype
• PMID 24529904

• Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice.

• Williams IM1, Wallom KL2, Smith DA2, Al Eisa N2, Smith C2, Platt FM3.Author information 1Dept. of Pharmacology, University of Oxford, UK. Electronic address: ian.williams@pharm.ox.ac.uk.2Dept. of Pharmacology, University of Oxford, UK.3Dept. of Pharmacology, University of Oxford, UK. Electronic address: frances.platt@pharm.ox.ac.uk.AbstractOBJECTIVES: Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1-/- mouse by combining three therapies that each targets unique aspects of the pathogenic cascade.
• Neurobiology of disease.Neurobiol Dis.2014 Mar 12;67C:9-17. doi: 10.1016/j.nbd.2014.03.001. [Epub ahead of print]
• OBJECTIVES: Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1
• PMID 24631719

• Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker.

• te Vruchte D, Speak AO, Wallom KL, Al Eisa N, Smith DA, Hendriksz CJ, Simmons L, Lachmann RH, Cousins A, Hartung R, Mengel E, Runz H, Beck M, Amraoui Y, Imrie J, Jacklin E, Riddick K, Yanjanin NM, Wassif CA, Rolfs A, Rimmele F, Wright N, Taylor C, Ramaswami U, Cox TM, Hastings C, Jiang X, Sidhu R, Ory DS, Arias B, Jeyakumar M, Sillence DJ, Wraith JE, Porter FD, Cortina-Borja M, Platt FM.AbstractLysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency–approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.
• The Journal of clinical investigation.J Clin Invest.2014 Mar 3;124(3):1320-8.
• Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we eva
• PMID 24487591

Japanese Journal

• Rapid quantification of miglustat in human plasma and cerebrospinal fluid by liquid chromatography coupled with tandem mass spectrometry

• GUITTON Jerome,COSTE Sylvie,GUFFON-FOUILHOUX Nathalie,COHEN Sabine,MANCHON Monique,GUILLAUMONT Marc
• Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 877(3), 149-154, 2009-01-15
• NAID 10028011801

• Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease

• ELSTEIN D.
• J. Inherit. Metab. Dis. 27, 757-766, 2004
• NAID 30012218671

Related Links

• Miglustat - Wikipedia, the free encyclopedia

Miglustat is a drug developed by Actelion and is used primarily to treat Type 1 Gaucher disease (GD1). It is marketed under the trade name Zavesca. Miglustat ( OGT 918, N-butyl-deoxynojirimycin) is an imino sugar (molecular weight: 219 ...

• ニーマン・ピックC型の治療法 - ニーマン・ピック病C型患者家族の会

Miglustat(ZavescaR)はスフィンゴ糖脂質合成の第一段階の触媒であるグルコシル セラミドシンターゼを可逆的に阻害し、ニーマン・ピックＣ型で蓄積しているガングリオシド の蓄積を減らします。そして血液脳関門を通過するため、脳のガンクリオシド蓄積による  ...

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★リンクテーブル★

リンク元

「ミグルスタット」

「ミグルスタット」

　　[★]

英

miglustat

商

ブレーザベス、Zavesca

関

ゴーシェ病、グルコシルセラミド

他に分類されない代謝性医薬品

• (グルコシルセラミド合成酵素阻害薬;I型ゴーシェ病治療
• a rarely used miscellaneous agent.

indications This drug is used to treat adults with mild to moderate type 1 Gaucher disease. contraindications Pregnancy and known hypersensitivity to this drug prohibit its use. Mosby's Medical Dictionary, 8th edition.

http://en.wikipedia.org/wiki/Miglustat http://www1.actelion.com/en/scientists/development-pipeline/phase-4/miglustat-zavesca.page